Low-level complex mosaic with multiple cell lines affecting the 18q21.31q21.32 region in a patient with de novo 18q terminal deletion

We describe a 5-year-old girl who was diagnosed at birth with 18q de novo homogeneous deletion at G-banding karyotype. Her clinical condition, characterized by hypotonia, psychomotor retardation, short stature, deafness secondary to bilateral atresia of the external auditory canals, was in agreement with the 18q deletion syndrome though presence of coloboma of a single eye only suggested a mosaic condition as an unusual sign. By combining multiple technologies including array-CGH, FISH, and WGS, we found that the terminal deletion 18q21.32q23 (21 Mb) was in segmental mosaicism of the proximal region 18q21.31q21.32 (2.7 Mb), which showed a variable number of copies: one, two, or three, in 7, 41 and 55% of the cells respectively. Breakpoint junction analysis demonstrated the presence of an inv-dup del (18q) with a disomic segment of 4.7 kb between the inverted and non-inverted copies of the duplicated region 18q21.31q21.32. From these results, we propose that all three types of abnormal chr18 (the inv-dup del and the two 18q terminal deletions of different sizes) arisen from breaks in a dicentric mirror chromosome 18q, either in more than one embryo cell or from subsequent breaking-fusion-bridge cycles. The duplication region was with identical polymorphisms as in all non-recurrent inv-dup del rearrangements though, in contrast with most of them, the 18q abnormality was of maternal origin. Taking into account that distal 18q deletions are not rarely associated with inv-dup del(18q) cell lines, and that the non-disjunction of chromosome 18 takes place especially at maternal meiosis II rather than meiosis I, multiple rescue events starting from trisomic zygotes could be considered alternative to the postmitotic ones. From the clinical point of view, our case, as well as those of del(18q) in mosaic with the dic(18q), shows that the final phenotype is the sum of the different cell lines that acted on embryonic development with signs typical of both the 18q deletion syndrome and trisomy 18. Asymmetrical malformations, such as coloboma of the iris only in the right eye, confirm the underlying mosaicism regardless of whether it is still detectable in the blood.     

An unusual chromosome 22q11 deletion associated with an apparent complementary ring chromosome in a phenotypically normal woman

We report an unusual chromosome 22q11 deletion associated with an apparent complementary ring chromosome in a phenotypically normal woman with a family medical history of 22q11 deletion. Using peripheral blood samples, conventional karyotyping, Fluorescence In Situ Hybridization (FISH) analysis on metaphase spreads and oligo array-based comparative genomic hybridization (oligo array-CGH) were performed. After conventional cytogenetic examination, the chromosome formula was as follows: 47,XX,+r(?)[16]/46,XX[6]. The FISH analysis revealed that this patient had a rearranged chromosome 22 with decreased centromeric fluorescence intensity and deletion of the 22q11.2 locus. She also had a supernumerary ring chromosome composed of an alpha-satellite centromere of 22 origin and 22q11.2 locus. The oligo array-CGH profile showed a deletion of approximately 4.18?Mb on chromosome 22 with a log 2 intensity ratio mean deviation of the deleted region of about -0.29. The 22q11 deletion associated with a complementary ring chromosome described in our patient could be consistent with a centromere misdivision mechanism, with one chromosomal break occurring in the alpha-satellite array and a second one in the 22q11 locus, a mechanism which has recently been referred to as the McClintock mechanism.     

Characterization by array-CGH of an interstitial de novo tandem 6p21.2p22.1 duplication in a boy with epilepsy and developmental delay

We report on a 6-years-old boy with psychomotor retardation, mild dysmorphic features and behavioral disturbances associated with epilepsy. Conventional cytogenetic analysis concluded to an interstitial de novo 6p21.2p22.3 duplication. Molecular cytogenetic analysis, including array-CGH technology, allows characterization of this 7.3Mb interstitial tandem duplication. The phenotype of this small 6p duplication reported to date is compared to other cases in the literature. Presence of epilepsy, although rare in patients with 6p duplication may be linked to genes involved in brain function and synaptic transmission in the 6p21.2p22.1 duplicated region (GABBR1, BRD2 and GRM4).     

Case report of rec(7)dup(7q)inv(7)(p22q22) and a review of the recombinants resulting from parental pericentric inversions on any chromosomes

We report a rare case of duplication for 7q22 → 7qter and deletion for 7p22 → 7pter, resulting from a meiotic recombination of a paternal pericentric inversion, inv(7)(p22q22). The newborn boy had the 7q trisomy syndrome. In addition, the diagnosis of chondrodysplasia punctata was made from lumbar and hand X-ray films taken soon after birth. Only two cases of rec(7)dup(7q), both in a single family, have been reported previously. We review 133 offspring with recombinations resulting from pericentric inversions on any chromosomes reported between 1981 and 1995. Of the 133 cases, 110 had a long-arm duplication and short-arm deletion, while only 23 had a short-arm duplication and long-arm deletion. In 85 of the 133 cases, the mother was an inversion carrier (five carriers had two affected offspring), and in 46, the carrier was a father (one carrier had three affected offspring). Kaiser [Hum Genet 1984;68:1–47] reviewed 63 offspring with recombinations derived from a parental pericentric inversion reported between 1972 and 1981. In both surveys, recombinations resulting from pericentric inversions of chromosomes 1, 12, 19, and Y were not found. Am. J. Med. Genet. 73:290–295, 1997. © 1997 Wiley-Liss, Inc.     

A case of a female infant with simultaneous occurrence of de novo terminal deletions on chromosome 14q and 20p

This is a case report on an infant with de novo terminal deletions on the long arm of chromosome 14 and on the short arm of chromosome 20 [46, XX, del(14)(q32)del(20)(p11)]. Examination revealed that the infant had a peculiar face, a cleft and high palate, abnormal dentition, butterfly-like vertebral defects, finger anomalies, a simian line on the left hand, talipes equinovarus, deep plantar furrows, abnormally high values of alkali phosphatase and lactate dehydrogenase, mild anemia and psychomotor retardation. Comparing the present case with previously reported cases of a single deletion on chromosome 14q or chromosome 20p, the infant showed some symptomatic and dysmorphic features of both deletions.     

Small supernumerary marker chromosome 15 and a ring chromosome 15 associated with a 15q26.3 deletion excluding the IGF1R gene

Array comparative genomic hybridization is essential in the investigation of chromosomal rearrangements associated with epilepsy, intellectual disability, and dysmorphic features. In many cases deletions, duplications, additional marker chromosomes, and ring chromosomes originating from chromosome 15 lead to abnormal phenotypes. We present a child with epilepsy, cardiac symptoms, severely delayed mental and growth development, behavioral disturbances and characteristic dysmorphic features showing a ring chromosome 15 and a small supernumerary marker chromosome. Array CGH detected a 1 Mb deletion of 15q26.3 in a ring chromosome 15 and a 2.6 Mb copy number gain of 15q11.2 corresponding to a small supernumerary marker chromosome involving proximal 15q. Our findings add to previously published results of 15q11q13 duplications and 15q26 terminal deletions. Based on our study we can support the previous reported limited information about the role of SELS, SNRPA1, and PCSK6 genes in the development of the heart morphology. On the other hand, we found that the copy number loss of our patient did not involve the IGF1R gene which is often associated with growth retardation (short stature and decreased weight). We hypothesize that haploinsufficiency of the 15q26 genomic region distal to IGF1R gene might be related to growth disturbance; however, presence of the ring chromosome 15 itself could also be responsible for the growth delay.

     

De novo direct tandem duplication of a small segment of the short arm of chromosome 7 (p21.22→22.1)

We report a boy with duplication of a small segment of the short arm of chromosome 7 (46, XY, dir dup (7) (p21.2→22.1). The boy presented with supravalvular pulmonary stenosis, atrial septum defect and mental retardation. The origin of the additional material from chromosome 7 was confirmed by fluorescence in situ hybridization. This technique in combination with the use of single-copy DNA probes may in future help to delineate the phenotype/karyotype correlation.     

Sub-band deletion of 7q36.3 in a patient with ring chromosome 7: Association with holoprosencephaly

We report on a patient with ring chromosome 7 analyzed by both high-resolution mid-prophase G-banding and fluorescence in situ hybridization (FISH) resolving a sub-band deletion of 7q36.3 associated with the clinical manifestation of holoprosencephaly (HPE). © 1996 Wiley-Liss, Inc.     

Small terminal deletion of 1p and duplication of 1q: Cytogenetics,FISH studies,and clinical observations at newborn and at age 16 years

A small, extra chromosome segment added to 1p was found by Q-banding 16 years ago in a newborn baby with low birth weight, short stature, wide open fontanelle, small palpebral fissures, depressed nose bridge, and inguinal hernia. This chromosome abnormality has been characterized recently with G-banding and fluorescence in situ hybridization using multiple DNA probes. The karyotype is now described as 46,XY, der(1)(qter→p36.13::q42.3→qter), representing a small deletion of 1p36.13-pter and a small duplication of 1q42.3-qter. Re-examination of this patient at age 16 years showed marked psychomotor delay, severely accentuated dorsal kyphosis and scoliosis, pectus excavatum, and other anomalies but no clinical signs of neuroblastoma. Comparison of the clinical findings in this case with those described in the patients having either a deletion of 1p36-pter or a duplication of 1q42-qter further illustrated the complexity of the genotype-phenotype relationship. Am. J. Med. Genet. 86:118–123, 1999. © 1999 Wiley-Liss, Inc.     

Unique de novo interstitial deletion of chromosome 17, del(17) (q23.2q24.3) in a female newborn with multiple congenital anomalies

We describe a newborn with a novel interstitial deletion of the long arm of chromosome 17 [del (17) (q23.2q24.3)] who died on day of life 17 during a recurrent apneic episode. Her phenotype included severe growth retardation, multiple facial anomalies, maldeveloped oralpharyngeal structures, and digital and widespread skeletal anomalies. This patient's phenotype was compared to two other reported patients with deletion 17q with minor clinical overlap consistent with a unique deletion. © 1995 Wiley-Liss, Inc.     

Interstitial deletion of chromosome 10, del(10) (q11.2q22.1) in a boy with developmental delay and multiple congenital anomalies

We describe a 4-year-old boy with an interstitial deletion of the long arm of chromosome 10:del(10) (q11.2q22.1). Frontal bossing, hypertelorism, bright blue iris color, up-slanting palpebral fissures, a flat nasal bridge, a broad nose, apparently low-set ears, micrognathia, deep philtrum, and hypotonia were noted neonatally. A murmur was noted at age 5½ months and surgical repair of subaortic stenosis was required at 4 years. At 4 years micrognathia was no longer evident, but the palate was high-arched. The pattern of abnormalities included postnatal-onset slow growth, short stature, mental retardation, and cardiac anomalies. © 1993 Wiley-Liss, Inc.     

Prenatal diagnosis of terminal deletion 7q and partial trisomy 3p in fetuses with holoprosencephaly

Chromosome aberrations, mendelian mutations and exogenous agents can cause holoprosencephaly. Therefore, etiologic evaluation of holoprosencephaly is necessary for obstetricians and genetic counselors, once a prenatal diagnosis of holoprosencephaly has been made. We present four pregnancies in three women in which routine sonographic examinations led to the prenatal diagnosis of holoprosencephaly. Prenatal cytogenetic analysis and fluorescence in situ hybridization demonstrated a 46, XY, del(7)(pter→q32:) and a 46, XY, der(2)t(2;3)(q37;p21)pat karyotype respectively in two fetuses with cyclopia, and a 46, XX, der(2)t(2;3)(q37;p21)pat and a 46, XX, der(7)t(3;7)(p23;q36) karyotype respectively in two fetuses with premaxillary agenesis. In conclusion, terminal deletion 7q and partial trisomy 3p in holoprosencephalic fetuses indicates that genes contributing to craniofacial development reside in these critical regions. Proper prognostic evaluation in further pregnancies requires expertise in cytogenetics and genetic counseling.     

Split foot and developmental retardation associated with a deletion of three microsatellite markers in 7q21.2-q22.1

A deletion of 7q21.2-q22.1 has been found in a patient with split foot and developmental retardation. Molecular analysis using polymerase chain reaction (PCR) showed deletion of three microsatellite markers, D7S527, D7S479 and D7S554, in the patient's paternal chromosome. These results pinpoint the critical region for an ectrodactyly locus (SHFD1) on chromosome 7.     

Fine mapping of a de novo interstitial 10q22-q23 duplication in a patient with congenital heart disease and microcephaly

In this study we report a female patient with an interstitial duplication of a region (10q22-q23) which is rarely reported in the literature. We fine mapped the aberration with array CGH, which revealed an 18.6-Mb duplication, covering 89 annotated genes, at 10q22.2-q23.33. There were no other deletions or duplications elsewhere in the genome. The main clinical features of the patient are microcephaly and congenital heart disease, which are likely to be caused by dosage effect of one or several genes in the duplicated region. Similar phenotypes have been found in other patients with 10q11-q22 duplications and in two out of three patients with 10q22-q25 duplications. However, most of the duplication cases were investigated only by conventional chromosome analyses, and fine mapping of these and other duplications of 10q22-q23 are warranted for genotype-phenotype comparisons.     

A novel 800 kb microduplication of chromosome 16q22.1 resulting in learning disability and epilepsy may explain phenotypic variability in a family with 15q13 microdeletion

The phenotype of 15q13.3 microdeletion is variable and can be non-penetrant. Recently, "second-hit hypothesis" has been proposed as a possible explanation for some variability in recurrent microdeletion syndromes. We present a family with a 1.9 Mb 15q13.3 deletion and a novel 800 kb 16q22.1 duplication. We show that the 16q22.1 duplication may be a phenotypic modifier in this family and likely results in epilepsy and learning difficulties. We state the possible genes in this region that may be important in neurological development and function.